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Lymphotoxin alpha eradicates acute myeloid leukemia and simultaneously promotes healthy hematopoiesis in mice

Acute myeloid leukemia (AML) is characterized by frequent relapse, which is driven by resistant leukemic stem or progenitor cells (LSCs). Here, we reported on a tumor-suppressive mechanism that can be harnessed to simultaneously clear LSCs and promote healthy hematopoiesis. Genetic deletion of the t...

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Hauptverfasser: Höckendorf, Ulrike (VerfasserIn) , Dutta, Sayantanee (VerfasserIn) , Kloos, Arnold (VerfasserIn) , Runtsch, Marah (VerfasserIn) , Zötsch, Carina (VerfasserIn) , Vosberg, Sebastian (VerfasserIn) , Wang, Yongjie (VerfasserIn) , Kienreich, Sophie (VerfasserIn) , Flasch, Bettina (VerfasserIn) , Malovan, Grazia (VerfasserIn) , Jäger, Vanessa (VerfasserIn) , Stanzer, Stefanie (VerfasserIn) , Prein, Stefanie (VerfasserIn) , Odinius, Timo O. (VerfasserIn) , Wagner, Celina V. (VerfasserIn) , Buschhorn, Lars (VerfasserIn) , Dill, Veronika (VerfasserIn) , Perfler, Bianca (VerfasserIn) , Haferlach, Torsten (VerfasserIn) , Döhner, Konstanze (VerfasserIn) , Götze, Katharina S. (VerfasserIn) , Ruland, Jürgen (VerfasserIn) , Bassermann, Florian (VerfasserIn) , Wahida, Adam (VerfasserIn) , Heikenwälder, Mathias (VerfasserIn) , Branca, Caterina (VerfasserIn) , Schmöllerl, Johannes (VerfasserIn) , Zuber, Johannes (VerfasserIn) , Burk, Ann-Cathrin (VerfasserIn) , Zeiser, Robert (VerfasserIn) , Sill, Heinz (VerfasserIn) , Jayavelu, Ashok Kumar (VerfasserIn) , Zebisch, Armin (VerfasserIn) , Heuser, Michael (VerfasserIn) , Dengler, Michael A. (VerfasserIn) , Jost, Philipp J. (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: November 2025
In: Science translational medicine
Year: 2025, Jahrgang: 17, Heft: 826, Pages: 1-15
ISSN:1946-6242
DOI:10.1126/scitranslmed.adu3313
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1126/scitranslmed.adu3313
Verlag, lizenzpflichtig, Volltext: https://www.science.org/doi/10.1126/scitranslmed.adu3313
Volltext
Verfasserangaben:Ulrike Höckendorf, Sayantanee Dutta, Arnold Kloos, Marah Runtsch, Carina Zötsch, Sebastian Vosberg, Yongjie Wang, Sophie Kienreich, Bettina Flasch, Grazia Malovan, Vanessa Jäger, Stefanie Stanzer, Stefanie Prein, Timo O. Odinius, Celina V. Wagner, Lars Buschhorn, Veronika Dill, Bianca Perfler, Torsten Haferlach, Konstanze Döhner, Katharina S. Götze, Jürgen Ruland, Florian Bassermann, Adam Wahida, Mathias Heikenwälder, Caterina Branca, Johannes Schmöllerl, Johannes Zuber, Ann-Cathrin Burk, Robert Zeiser, Heinz Sill, Ashok Kumar Jayavelu, Armin Zebisch, Michael Heuser, Michael A. Dengler, Philipp J. Jost

MARC

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520 |a Acute myeloid leukemia (AML) is characterized by frequent relapse, which is driven by resistant leukemic stem or progenitor cells (LSCs). Here, we reported on a tumor-suppressive mechanism that can be harnessed to simultaneously clear LSCs and promote healthy hematopoiesis. Genetic deletion of the tumor necrosis factor (TNF) superfamily member lymphotoxin alpha (Lta) blocked cell death and accelerated leukemogenesis in murine AML models. Accordingly, exposure of leukemic cells to exogenous recombinant lymphotoxin alpha (LTα3) induced myeloid differentiation and, in part, cell death in AML progenitors. In syngeneic and patient-derived xenograft mouse models, exposure to recombinant LTα3 resulted in deep and durable remissions. LTα3 repressed leukemia by depleting tumor necrosis factor receptor (TNFR)-associated factor 2 (TRAF2) through activation of TNF receptors TNFR1 and TNFR2. In contrast with conventional therapies, LTα3 exerted only minimal toxicity on the healthy hematopoiesis but instead promoted hematopoietic progenitors. Leveraging this endogenous tumor-suppressive mechanism may decouple treatment efficacy on malignant cells from undesired bone marrow suppression. 
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